Process for the production of carboxamides of oxo-1,2-benzothiazine-1,1-dioxides

ABSTRACT

Disclosed herein is an improved process for the production of carboxamides of 3,4-dihydro-oxo-1,2-benzothiazine-1,1-dioxides. Said process comprises contacting either a 3-oxo- or 4-oxo-1,2benzothiazine-1,1-dioxide with a known or readily prepared phenylisocyanate to produce the corresponding 4- or 3carboxanilide followed by a transamidation with an amine whose own isocyanate is frequently unstable to produce carboxamide with previously disclosed pharmaceutical value as a non-steroidal anti-inflammatory agent.

I United States Patent [1 1 [111 3 89mm Lombardino June 24 W75 [54] PROCESS FOR THE PRODUCTION OF 3,853,862 12/1974 Lombardino 260/243 CARBOXAMIDES OF OXO-l,2-BENZOTHIAZINE-l,l-DIOXIDES Z y lfl Y d H [[0 Z, I O O i; [75] Inventor: Joseph G. Lombardino, Niantic, me} gen 0 Wm nn y an u Z 57 ABSTRACT [73] Asslgnee: Pfizer New York Disclosed herein is an improved process for the pro- 22 Filed; Oct. 1 1974 duction of carboxamides of 3,4-dihydro-oxo-1,2-

benzothiazine-l,l-dioxides. Said process comprises {21] Appl- N05 510,892 contacting either a 3-oxoor 4-0X0-1,2-benz0thiazinel,l-dioxide with a known or readily prepared 52 us. Cl. 260/243 R; 424/246 phenylisocyanate to Produce the Corresponding Or [51] Int. Cl C07d 93/02 3'carboxanilide followed y a transamidation with an [58] Field of Search 260/243 R amine Whose Own isocyanate is frequently unstable to produce carboxamide with previously disclosed phar- [56] References Cited maceutical value as a non-steroidal anti-inflammatory agent 10 Claims No Drawings PROCESS FOR THE PRODUCTION OF CARBOXAMIDES OF OX-1,Z-BENZOTHIAZINE-l,l-DIOXIDES BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a process for the production of carboxamides of benzothiazine dioxides which have been found to be valuable anti-innflammatory agents that do not produce the undesirable side-effects frequently experienced with corticosteroids, such compounds are described in my commonly assigned US. Pat. No. 3,591,584, issued July 6, 1971, the disclosure of which is incorporated herein by reference. In particular, it relates to an improved chemical process for the production of N-substituted-3,4-dihydro-2-substituted- 4-oxo-2I-I- l ,2-benzothiazine-3-carboxamidel l dioxides and N-substituted-3,4-dihydro-2-substituted- 3-oxo-2H-l ,2-benzothiazine-4-carboxamide-l,1- dioxide wherein the N-substituent is a heterocyclic moiety.

2. Description of the Prior Art As disclosed in US. Pat. No. 3,591,584, two routes are available for the synthesis of N-substitutedbenzothiazine-carboxamides. The first, used wherein the moiety is not a heterocycle, comprises contacting a compound of the general formula OUJ I II

organic isocyanate of the formula R NCO wherein R is selected from the group consisting of hydrogen, alkyl having one to eight carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety phenyl, substituted phenyl and naphthyl to produce a compound of the general structural formula The second method was employed in the preparation of those compounds wherein the N-substituent is a heterocyclic moiety such as substituted or unsubstituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolonyl, thiazolyl,isothiazolyl, benzothiazolyl, benzoxazolyl or thiadiazolyl. The isocyanate route was not used to prepare these compounds because the requisite heterocyclic isocyanates are either unstable or extremely difficult to synthesize. The 4-carboxamides were instead prepared from compounds of Formula III or [V wherein R is a mono-, dior unsubstituted phenyl and the substituents are chosen from the group consisting of fluorine, chlorine, bromine, nitro, trifluoromethyl and alkyl and alkoxy having from one to three carbon atoms. Said compounds were contacted with an alcohol to form the corresponding 3- or 4-carboxylic acid ester by the alcoholysis method well-known to those skilled in the art. The 3-carboxamides were prepared from known compounds such as a 3-oxo-l,2-benzothiazoline-2-acetic acid ester, [Chemische Berichte, vol. 30, p. 1267 (1897).] Said benzothiazoline were treated with an alkali metal alkoxide like sodium methoxide in a polar solvent such as dimethylsulfoxide or dimethylformamide whereby they rearrange to the corresponding 3 ,4-dihydro-4-oxo-2ll-l-1,2-benzothiazine-3- carboxylate-l,l-dioxide ester. [Journal of Organic Chemistry, vol. 30, p. 2241 (1965).] This compound is then treated with an alkyl halide, preferably an iodide, wherein the alkyl group is identical with R to yield the desired ester. Said 3- and 4-esters were then contacted with at least an equimolar amount of an amine of the general formula R NH wherein R is one of the heterocyclic moieties of interest to produce the desired benzothiazine carboxamide which is N-substituted with a heterocyclic moiety. Standard ammonolysis procedures known to those skilled in the art of organic chemistry were employed.

SUMMARY OF THE INVENTION The process of this invention for producing a 3,4- dihydro-Zl-ll-l,Z-benzothiazine-l,l-dioxide of the formula wherein X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl and alkyl and alkoxy each having from one to five carbon atoms; R, is a member selected from the group consisting of hydro-,

gen, alkyl having from one to six carbon atoms, alkenyl having up to four carbon atoms, and phenylalkyl having up to three carbon atoms in the alkyl moiety;

and R is a member selected from the group consisting of Z-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2- pyridyl, 5-met hyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-chloro-2-pyridyl, 5-bromo-2- pyridyl, 5-nitro-2-pyridyl, 3-hydroxy-2-pyridyl, S-carboxamido-2-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4,5-dimethyl-2-pyrimidyl, 4-pyrimidyl, 5-methyl-3- pyrazinyl, 6-methoxy-3-pyridazinyl l-phenyl-3- pyrazolonyl,"'2-thiazolyl, 4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, S-bromo-2-thiazolyl, 4,5-dimethyl-2- thiazolyl, 3-isothiazolyl, 2-benzothiazolyl, 6-methyl-2- benzothiazolyl, 4-chloro-2-benzothiazolyl, 6-bromo-2- benzothiazolyl, 5-chloro-2-benzoxazolyl, l ,3 ,4- thiadiazolyl, S-methyl-l,2,4-thiadiazolyl, S-methyl- 1,3,4-thiadiazolyl, 1,2,4-triazolyl and 6-phenyl-l,2,4- triazolyl comprises:

contacting a carboxanilide of the general structural formula wherein.A and B are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl and alkyl and alkoxy each having from one to three carbon atoms and X, Y and R are all as previously defined;

with an amine of the formula R NI-I wherein R is also as previously defined in a reaction-inert medium at a temperature between about 75 and 200C. to produce either a 3,4-dihydro-2-substituted-4-oxo-N-acyl- 2I-I-l ,2-benzothiazine-3-carboxamide-l l-dioxide or 3 ,4-dihydro-2-substituted-3 -o'xo-N-acyl-2I-I-l ,2- benzothiazine-4-carboxamide-l,l-dioxide wherein the acyl moiety is a heterocycle as defined above.

The preferred products of the process of this invention are the 3-carboxamides especially those wherein R is 2-thiazolyl or 2-pyridyl. Other preferred products are those 3-carboxamides wherein X and Y are each hydrogen and R, is methyl. Preferred starting materials are those of Formula VII wherein either of said A or B is other than hydrogen and located at the ortho position. Preferred substituents are chlorine and methoxy.

Especiallyrpreferred;as.-;? starting material is the compound of Formula VII;wherein-R .is methyl, A is 2- chloro'and Bis-5 -chloro. I

The pro cessof the instant invention is superior to the prior ar tlin that: substitutes a transamidation for an alcohololysis followed .by'an ammonolysis. Thus, compounds-0f FormulaeVll and VIII can be converted in asinglestep to those of Formulae V and VI respectively. The need for the preparation of the 3- or 4- carboxylic acid ester in an intermediate step is thereby obviated. The products of the process of the instant invention are valuable as non-steroidal anti-inflammatory agents.

DETAILED DESCRIPTION OF THE INVENTION In the preferred embodiment, a carboxanilide of Formula VII or VIII is dissolved in a reaction-inert solvent at a concentration of at least 0.5% by weight. Reactioninert solvents are those which are substantially free of adverse effects on reactants and products under the reaction condition employed. An example of such solvents are the xylye nes. To this reaction mixture is added at least one equivalent of a heterocyclic amine of the formula R NH Preferably, at least two equivalents of said amine are employed. Said mixture is then refluxed under nitrogen until the reaction is substantially complete. This process usually requires about two days, said reaction mixture is then evaporated in vacuo to yield a gum-like solid residue, said residue is then dissolved in a minimum amount of boiling isopropanol or other suitable solvents for recrystallization well known to those skilled in the art. The solutionis then cooled to about 0C. and maintained there as a precipitate forms. The precipitate is then filtered and air dried.

- The carboxanilides ofFormula VII or VIII are prepared by contacting a phenylisocyanate bearing said A and B substituents with a benzothiazine of the Formula I or II respectively. This particular reaction is normally carried out in a basic solvent medium, most desirably employing a reaction-inert organic solvent such as tetrahydrofuran, a dimethylsulfoxide or dimethylformamide andpreferably using a slight molar excess of a base such as triethylamine, which may be admixed with 'the solvent. Many of the aforesaid isocyanate reagents are either known compounds or else they can easily be prepared, using methods well-known to those skilled in the art, starting from readily available materials. In practice, it is usually preferable to employ at least about a molar equivalent .of the isocyanate reagent in the instant reaction of the present invention, with best results often being achieved by using just a slight excess of same. Although any temperature below that of reflux may be used in order to effect the reaction, it is normally found most convenient to employ elevated temperatures in almost every case, so as to shorten the re- 1 cipitates from solution and is subsequently collected by 'such means as suction filtration and the like.

The preparation of compounds of Formula I through the sodium allcoxide isomerization of saccharin derivatives has been discussed in detail in 1-1. Zinnes et al., Journal of Organic Chemistry, 31, 162 (1966). The 3-oxo compounds of Formula 11 are prepared using 0- toluene sulfonamide as a starting material. For example, the compound wherein R is methyl is prepared by reacting N-rnethyl o-toluene sulfonamide with nbuty1 lithium followed by aqueous mineral acid to afford 2-(N-methylsulfamyl) phenylacetic acid which is then treated with p-toluenesulfonic acid to produce 3,4- dihydro-2methyl-3-oxo-2H-1 ,2-benzothiazine-l ,1- dioxide.

EXAMPLE 1 3,4-Dihydro-2-Methyl-4-Oxo-2ll-l-1,Z-Benzothiazine- 3Carboxanilide-l 1 -Dioxide ln a round-bottomed three-necked flask fitted with reflux condenser, magnetic stirrer, dropping funnel and gas-inlet tube, there were placed 0.082 g. (0.0017 mole) of a 50% dispersion of sodium hydride in a mineral oil, said dispersion having been washed in nhexane and the residue, after decantation, suspended in 3 ml. of dry dimethylformamide while under a dry nitrogen atmosphere. Stirring was then commenced and to the resulting gray suspension, there were then added dropwise a combination consisting of 0.316 g. (0.0015 mole) of 3,4-dihydro-2-methyl-4-oxo-2l-l-1,2- benzothiazine 1,1dioxide [l-l. Zinnes et al., J. Org. Chem., Vol. 31, p. 162 (1966)] and 0.178 g. (0.0015 mole) of phenyl isocyanate dissolved in 3 ml. of dry dimethylformamide. Foaming and gas evolution occurred during the addition step and when the latter was complete, the reaction mixture was stirred at room temperature (-25C.) for a period of minutes and then poured into 15 ml. of cold 3 N hydrochloric acid. The resulting pale yellow precipitate was filtered and then vacuum dried to afford 302 mg. of material melting at 205215C. After one recrystallization from isopropanol, there was obtained 208 mg. (42%) of 3,4- dihydro-2-methyl-4-oxo-2l-l-1,2-benzothiazine-3- carboxanilide 1,1-dioxide, MP. 213215C.

Analysis.Calcd. for C H N OS (percent): C,58.17; l-ll,4.27; N,8.48. Found (percent): (1,5814; ll,4.33; N,8.14.

EXAMPLE ll 2,5 -Dichloro-3,4-Dihydro-2-Methyl-4-Oxo-2l-l- 1 ,2- Benzothiazine-3-Carboxanilide-1,l-Dioxide The procedure described in Example 1 was repeated using 0.576 g. (0.012 mole) of 50% sodium hydride-oil (hexane-washed) in 15 ml. of dry dimethylformamide, 2.53 g. (0.012 mole) of 3,4-dihydro-2-rnethyl-4-oxo- 2l1'l-1,2-ben20thiazine 1,1-dioxide and 2.26 g. (0.012 mole) of 2,5-dichlorophenyl isocyanate in m1. of dry dimethylformamide. Upon completion of the reaction, the resulting mixture was poured into 140 ml. of iced 3 N hydrochloric acid and filtered. The heavy yellow precipitate collected in this manner was then air dried and subsequently dissolved in boiling ethanol, from which pale yellow crystals of 2',5-dichloro-3,4- dihydro-2-methyl-4-oxo-2H-1,2-benZothiazine-3- carboxanilide 1,1-dioxide (MP. 223225C.) soon deposited on slow cooling. The yield of product amounted to 678 mg. (14%).

Analysis.Calcd. for C l-l Cl N O S (percent): C,48.13; ll,3.03; l l,7.02. Found (percent): @4809; l-ll,3.l0;1\l,6.95.

EXAMPLE lll Substituted-3,4-Dihydro-2-Methyl-4-Oxo-2l-l-1,2-

Benzothiazine-3-Carboxanilide-1,l-Dioxides The procedure described in Example 1 was repeated to prepare the following 3,4-dihydro-2-methyl-4-oxo- 21-1-1,2-benzothiazine-3-carboxamide 1,1-dioxides, starting from 3,4-dihydro-2-methyl-4-oxo-21-1-l,2 benzothiazine 1,1-dioxide and the appropriate organic isocyanate reagent in each case:

4-chloro-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-

benzothiazine-3-carboxanilide 1,1-dioxide, 230232C. 2-methoxy-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-

benzothiazine-3carboxanilide, 1,1-clioxide, MP. 178180C. 4-methoxy-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-

benzothiazine-3-carboxanilide 1,1-dioxide, MP. 250-252C. 2'-methyl-3,4-dihydro2-rnethyl-4'oxo-2ll -l ,2-

benzothiazine-3-carboxani1ide 1,1-dioxide, MP. 157160C. 4'-methyl-3 ,4-dihydro-2-methyl-4-oxo-2Hll ,2-

benzothiazine-3-carboxanilide 1,1-dioxide, MP.

234-236C. 3-trifluoromethyl-3,4-dihydro-2-methyl-4-oxo-2H- 1,2-benzothiazine-3-carboxanilide 1,1-dioxide, MP. l198C. 3'-chloro-3,4-dihydro-2-methyl-4-oxo-2H-1,2- benzothiazine-3-carboxanilide 1,1-dioxide, 267-269C. (dec.) 3',4-dichloro-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-

EXAMPLE 1V Substituted-3 ,4-Dihydro-2Methyl-4-Oxo-21Hl-1,2- Benzothiazine-3-Carboxanilide-1 1 -Di0xides The procedure described in Example I is employed to prepare the following 3-carboxamide compounds starting from the corresponding 3,4-dihydro-4-oxo-2l-ll-1,2- benzothiazine l,1-dioxide and the appropriate organic isocyanate or isothiocyanate reagent in each case:

3,4-Dihydro 2-Methyl-3 Oxo-2H- l ,2-Benzothiazinel l -Dioxide [n a round-bottomed flask (equipped with magnetic stirrer) under a dry nitrogen atmosphere, there were placed 31.4 g. (0.17 mole) of N-methyl otoluenesulfonamide dissolved in 600 ml. of dry tetrahydrofuran. This solution was cooled to C., at which point 219 ml. of n-butyl lithium (1.6 M) in n-hexane' for seventy minutes, at which point 500 m1. of water,

were added and the aqueous mixture thus obtained was subsequently acidified with 700 ml. of concentrated hydrochloric acid. The so-acidifiedaqueous solution was then concentrated in vacuo to one-third of its original volume and a white solid precipitate soon deposited from the concentrate on cooling to room temperature.

. The latter solid material was subsequently collected by means of suction filtration and air dried to constant weight to afford 29.1 g. (75%) of Z-(N-methylsulfamyl)phenylacetic acid, M.P. l58l64C.

0 0 ll C-WHR,

X Y R, R,

5-CH; H phenyl C,H (CH,), 6-OCH, H o-nitrophenyl isoC H-, H 8-Cl m-nitrophenyl C,H 5Cl H p-nitrophenyl methallyl H 7OCH;, 2-chlorophenyl isoC H 6-Cl 7Cl 3-chlorophenyl nC,H-, 5Br H 4-chlorophenyl C H CH, 5(n-C H,) H 2-methylphenyl methallyl 6OC,H H 3-methylphenyl isoC H 8-Br 4-methylphenyl' C H CH 6-Cl H Z-methoxyphenyl C 5 6-Br H 4-methoxyphenyl allyl 6CH;, 7CH 2,5-dichlorophenyl n--C,H 6-0CH; 7OCH, 3,4-dimethy1phenyl CQH5CH2 H H 3,4-dichlorophenyl iso-QH H 8Cl 4-(n-butyl)phenyl CH H H 3-CF;, phenyl methallyl 5-CH;, H 2,4-dimethoxypheny1 C,H,, H 8(nC,H,) 2,5-dimethoxyphenyl C H CH H H 2-ethoxyphenyl isoC H 6-OCH H (n) ,7--OC H (n) 4-ethoxyphenyl allyl H H 3-isopropoxyphenyl CH,

6-F 7F 4-bromophenyl C H (CH H H 4-fluorophenyl nC,H, 6-CF 7CF 2,3-dichlorophenyl C H CH, 6-Cl H 5-Cl-2-methoxyphenyl C,H 6-Br 7-Br 3,5-dichlorophenyl iso-QH, 5CH H 3,5-dimethoxyphenyl C H CH, H 7OC,,H 2,6-dimethylphenyl methallyl 6(nC H 7-( in-C H 2-CH,O-S-methylphenyl 3 H 8-NO, 2,4-dimethylphenyl iso-C H H H 3-Cl-4-methylphenyl C H,(CH,), 5--OCH H 2-Cl-5-CF phenyl 5 EXAMPLE v To a solution of-29.0 g. (0.13 mole) of the above acid in 1500 ml. of dry benzene, there were added approximately mg. of p-toluenesulfonic acid. The entire system was contained in a round-bottomed flask, equipped with reflux condenser, Dean Stark trap and a drying tube. The solution was then heated to the boiling point and refluxed for 2 hours thereafterwards, at which point 3.0 ml. of water had separated (i.e., was removed from the reaction mixture). After filtering the hot solution to remove any physical impurities, the resulting filtrate was concentrated in vacuo to near dry EXAMPLE VI 2-Chloro-3,4-Dihydro-2-Methyl-3-Oxo-2H-.l ,2- Benzothiazine-4-Carboxanilide-1,1-Dioxide The procedure described in Example I was followed except that 3.09 g. (0.0143 mole) of 3,4-dihydro-2- methyl-3-oxo-2-H-1,2-benzothiazine 1,1-dioxide in 20 ml. of dimethylsulfoxide was reacted with 2.2 g. (0.0143 mole) of o-chlorophenyl isocyanate in the presence of 1.45 g. (0.0143 mole) of triethylamine (in place of 50% sodium hydride). The resulting mixture 4-methoxy-3,4-dihydro-2-methyl-3-oxo-2H-1,2-

benzothiazine-4-carboxanilide 1,1-dioxide, MP. 164l 67C.

4-nitro-3 ,4-dihydro-2-methyl-3-oxo-2H- l ,2-

was flushed with nitrogen and then stirred at room tembezotbialine-4-Cafb0Xaflilide perature (-25C.) for a period of 20 hours. After pouring the stirred reaction mass into 100 ml. of 3 N hydroy y y chloric acid at 0C., there was obtained a yellow prebenZOthiaZine-4-arb0Xanilide L cipitate which was subsequently collected by means of 1 17042000 suction filtration, washed with cold water and dried. y- #ty qhy m- The latter material was then dissolved in hot boiling benzothlazme4carboxamhde LLdlOXlde,

benzene, and the solution which formed was subsequently filtered while hot and allowed to cool to room 3 j' i l Q 'F temperature on standing. In this manner, there were benfothlafmeA"cal'boxamllde obtained 2.39 g. 49% of 2-chloro-3,4-dihydro-2- 477 C 1,1-dioxide in the form ofa crystalline deposit, melting benzothlazme'4'carboxamhde ll'dloxlder at 139-141c.

Analysis.Calcd. for c n cm os (percent): l 9- Y m y -q ,2- C,52 67; H359; Found (percent): (3,5291; benzothiazme-4-carboxanilide 1,1-d1ox1de, M.lP. H,3.68; N,7.77.

2'-methoxy-3,4-dihydro-2-methyl-3-oxo-2l-lll ,2- EXAMPLE VH benzothiazine-4-carboxanilide 1,1-dioxide, MP.

157159C. Substituted-3,4-Dihydro-3-Oxo-2Hl ,Z-Benzothiazine- 3lr4l'dichlom'3 4 carboxanilide l 1 Di0Xide benzothiazine-4-carboxanilide l,l-dioxide, MP.

The procedure described in Example I was repeated to prepare the f l 1,Z-benzothiazine-4-carboxanilide 1,1-dioxide, ZH-l,2-benzoth1az1ne-4-carboxamide 1,1-dioxides,

Startmg fi 3f4 (}lhydro z methyl 39X0-2H-12' 4-bromo-3,4-dihydro-3-oxo-2Hl-l ,2-benzothiazinebenzothiazine l,1-d1ox1de and the appropriate organic 4 carboxanilide l,Ldioxide Mp isocyanate reagent, and usmg trrethylam ne in place of Sodlum hydr'de (on the Same molar basls) as catalyst benzothiazine-4-carboxanilide-l,l-dioxide, MP. in each case: 162046500 3 ,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine- 4-carboxanilide l,l-dioxide, M.P. l54l56C. I 4-fluoro-3,4-dihydro-2-methyl-3-oxo-2H-1,2- EXAMPLE benzothiazine-4-carboxanilide 1,1-dioxide, MP. 40 149 1 5 1C. Substituted-3,4-Dihydro-3-Oxo-2H-l ,Z-Benzothiazine- 4-chloro-3,4-dihydro-2-methyl-3-oxo-2l-ll-1,2- 4-Carboxanilide-1, l-lDioxide.

benzothiazine-4-carboxanilide 1,1-dioxide, MP. l39l4lC. (dec.) The procedure described in Example I is employed 3-trifluoromethyl-3,4-dihydro-2-methyl-3-oxo-2H- once again, with triethylamine replacing sodium hyl,Z-benzothiazine-4-carboxanilide 1,1-dioxide. dride as the catalyst (on the same molar basis and this MP. l30-133C. time to prepare the following 4-carboxamide com- 4-methyl-3,4-dihydro-2-methyl-3-oXo-2l-ll-1 ,2- pounds, starting from the corresponding 3,4-dihydro-3- benzothiazine-4-carboxanilide 1,1-dioxide, Ml. oxo-Zlll-LZ-benzothiazine 1,1-di0xide and the appro- 15l153C. priate organic isocyanate reagent in each instance:

X Y R 5CH3 H phenyl CBH5(CH2)2 6OCH3 H o-nitrophenyl isoC;,H H 8-Cl m-nitrophenyl CZHS 5-Cl H p-nitrophenyl methallyl H 7-OCl-l Z-chlorophenyl isoC H 6Cl 7Cl 3-chlorophenyl nC H 5F H 4 chlorophenyl CGHSCHZ 5-( nC H H Z-methylphenyl methallyl Continued X Y R, R.

6OC,H. H 3-methylphenyl iso-C,H, H B-Cl d-methylphenyl C H,(CH,), 6Cl H Z-methoxyphenyl Q5, 6-F H 4-methoxyphenyl allyl 6-CH; 7CH, 2,5-dichlorophenyl n-C H 6--0CH, 7OCH, 3.4-dimethylphcnyl C.H,CH, H 3,4-dichlorophenyl iso-CJ-l, H 8-Cl 4-(n-butyl)phenyl CH, H H 3-CF,phenyl mcthallyl 5-CH, H 2,4-dimethoxyphenyl C,H,, H 8-(n-C.H.) 2,5-dimethoxyphenyl C,H,CH, H H Z-ethoxyphenyl iso-C,H

6OC H (n) 7OC ,H (n) 4-ethoxyphenyl allyl H H 3-isopropoxyphenyl CH, 6-F 7F 4-bromophenyl C.H,(CH,), H H 4-fluorophenyl n--C,H, 6-CF; 7-CF, 2.3-dichlorophcnyl C.H.CH, 6-Cl H S-Cl-Z-mcthoxyphenyl ,H, 6Cl 7-Cl 3.5-dichlorophenyl iso-QH, S-CF, H 3.5 -dimethoxyphenyl C.H,CH,

H 7OC H 2,6-dimethylphenyl methallyl 6(nC H||) 7( nC;H 2-CH,O-5-methylphenyl CH, H 8-NO, 2.4-dimethylphenyl n-C.H, H H 3-Cl-4-methylphenyl C H,(CH,),

EXAMPLE IX EXAMPLE X N-( 2-Thiazolyl )-3 ,4-Dihydro-2-Meth yl-4-Oxo-2H l ,2- Benzothiazine-3-C arboxamide-l l -Dioxide In a round-bottomed flask under nitrogen were placed xylene (10 ml.), 2,5-dichloro-3,4-dihydro-2- methyl-4-oxo-2l-ll-l ,2-benzothiazine-3 -carboxanilide- 1,1-dioxide (0.100 g. 0.25 moles) prepared by the method of Example II, 2-aminothiazole (0.030 g., 0.30 mmoles) which is available from Aldrich Chemical Company, No. 12,312-9 (97% pure) and a trace of p-toluenesulfonic acid. The 2-aminothiazole was recrystallized from benzene before it was used. The reaction mixture was refluxed and the extent of the reaction was measured by thin layer chromatography. After 3.5 hours, no change was observed in the chromatogram. After mixture was stirred over the weekend at room temperature, the chromatogram showed a spot which aligned with that of the desired product. 2- Aminothiazole (0.030 g., 0.30 mmoles) and another trace of p-toluenesulfonic acid were added and the reaction mixture stirred overnight at room temperature. The mixture was then refluxed overnight. After sixteen hours, 2-aminothiazole (0.030 g., 0.030 mmoles) was added and the reflux continued for eight hours. Then, more Z-aminothiazole (0.060 g., 0.60 mmoles) was added and the reflux continued overnight. The reaction mixture was then evaporated in vacuo to half-volume and cooled to about 0C. whereupon a gummy brown precipitate formed. The mixture was evaporated to dryness and the solid residue dissolved in a minimum amount of boiling isopropanol, filtered and cooled to about 0C. The precipitate which formed was separated by filtration and air dried to yield crude N-(2- thiazolyl )-3 ,4-dihydro-2-methyl-4-oxo-2H-l ,2-

benzothiazine-3-carboxamide-l,l-dioxide (0.046 g., I 45%) M.P. 2l9-257. A further recrystallization from N-( 2-Thiazolyl )-3 ,4-Dihydro-2-Methy]-4-Oxo-2H-l ,2- Benzothiazine-3-Carboxamidel l-Dioxide In a round-bottomed flask under nitrogen was placed xylene (10 ml.) 2'-chloro-3,4-dihydro-2-methyl-4-oxo- 2l-l-l ,2-benzothiazine-3 carboxanilide-l l -dioxide (0.10 g., 0.27 mmoles) prepared by the method of Example lll, 2-aminothiazole (0.041 g., 0.41 mmoles) and a trace of p-toluenesulfonic acid. The mixture was refluxed overnight and 2-aminothiazole (0.041 g., 0.41 mmoles) added again. After another overnight reflux, more 2-aminothiazole (0.081 g., 0.82 mmoles) and the mixture again refluxedovernight. The mixture was then cooled to about 0C. and evaporated in vacuo to afford a gummy semi-solid which was dissolved in a minimum amount of boiling isopropanol. The mixture was filtered, cooled to about 0C. and filtered again to separate the precipitate which formed. ,The air-driedsolid residue (0.039 g'.) M.P. -l98202 C., was shown by thin layer chromatography to be about a 50% mixture of the title compound with starting material.

EXAMPLE XI N-Substituted-3 ,4-dihydro-2-Methyl-4-Oxo-2H-l ,2- Benzothiazine-3-Carboxanidesl l -Dioxide The carboxanilides of Examples II, III and IV are reacted with amines of the structure R Nl-l in accordance with the methods of Examples IX and X to produce compounds of the structure CNHR wherein R is chosen from the group consisting of 2- pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl,

S-methyI-Z-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl- Z-pyridyl, 5-chloro-2-pyridyl, 5-bromo-2-pyridyl, 5- nitro-Z-pyridyl, 3-hydroxy-2-pyridyl, 5-carboxamido-2- pyridyl, Z-pyrazinyl, Z-pyrimidyl, 4,5-dimethyl-2- pyrimidyl, 4-pyrimidyl, 5-methyl-3-pyrazinyl, 6- methoxy-3-pyridazinyl, l-phenyl-3-pyrazolonyl, 2-

thiazolyl, 4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, 5-bromo-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 3- isothiazolyl, 2-benzothiazolyl, 6-methyl-2- benzothiazolyl, 4-chloro-2-benzothiazolyl, 6-bromo-2- benzothiazolyl, 5-chloro-2-benzoxazolyl, 1,3 ,4- thiadiazolyl, S-methyl-l,2,4-thiadiazolyl, S-methyl- 1,3,4-thiadiazolyl, l,2,4-triazolyl and 6-phenyl-l,2,4- triazolyl.

EXAMPLE XII N-Substituted-3,4-Dihydro-2-Methyl-3-Oxo-2l-I-1 ,2- Benzothiazine-4-Carboxamides-1,1-Dioxide The carboxanilides of Examples VI, VII and VIII are reacted with amines of the structure R NI-I in accordance with the methods of Examples IX and X to produce compounds of the structure wherein R is chosen from the group consisting of 2- pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, S-methyl-Z-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl- Z-pyridyl, 5-chloro-2-pyridyl, 5-bromo-2-pyridyl, 5- nitro-Z-pyridyl, 3-hydroxy-2-pyridyl, S-carboxamido-Z- pyridyl, 2-pyrazinyl, Z-pyrimidyl, 4,5-dimethyl-2- pyrimidyl, 4-pyrimidyl, 5-methyl-3-pyrazinyl, 6- methoxy-3-pyridazinyl, l-phenyl-3-pyrazolonyl, 2-

thiazolyl, 4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, S-bromo-Z-thiazolyl, 4,5-dimethyl-2-thiazolyl, 3- isothiazolyl, 2-benzothiazolyl, 6-methyl-2- benzothiazolyl, 4-chloro-2-benzothiazolyl, 6-bromo-2- benzothiazolyl, 5-chloro-2-benzoxazolyl, 1,3 ,4- thiadiazolyl, S-methyl-l,2,4-thiadiazolyl, S-methyl- 1,3,4-thiadiazolyl, 1,2,4-triazolyl and 6-phenyl-l,2,4- triazolyl.

What is claimed is:

1. A process for preparing a 3,4-dihydro-2l-lI-l,2- benzothiazine 1,1-dioxide of the formula:

i f O wherein X and Y each are selected from the group consisting of hydrogen, fluorine, chlorine, brothiadiazolyl, S-methyl-1,2,4-thiadiazolyl, S-methyl- 1,3 ,4-thiadiazolyl, 1,2,4-triazolyl;

which comprises contacting a corresponding carboxanilide compound of the formulae:

1,2,4-triazolyl and 6-phenyland wherein A and B are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl and alkyl and alkoxy of up to three carbon atoms, with at least a substantially equimolar portion of an amine of the formula lR Nli wherein R is as previously defined in reaction-inert organic solvent medium at a temperature between about C. and about 200C. until the reaction is substantially complete.

2. The process of claim 11 wherein A is other than hydrogen and is located at the ortho position of the phenyl ring.

3. The process of claim 2 wherein A. is chlorine.

4. The process of claim 2 wherein A is methoxy.

5. The process of claim 3 wherein 1B is S-chloron.

6. The process of claim 2 wherein said starting material is a 3-carboxanilide and X and Y are each hydrogen and 1R is methyl.

7. The process of claim 6 wherein R is 2-thiazolyl.

8. The process of claim 6 wherein R is 2-pyridyl.

9. The process of claim 6 wherein A is 2-chloro and B is S-chloro.

T0. The process of claim 6 wherein A is 2-methoxy and 1B is S-methoxy. 

1. A PROCESS FOR PREPARING A 3,4-DIHYDRO-2H-1,2-BENZOTHIAZINE 1,1-DIOXIDE OF THE FORMULA:
 2. The process of claim 1 wherein A is other than hydrogen and is located at the ortho position of the phenyl ring.
 3. The process of claim 2 wherein A is chlorine.
 4. The process of claim 2 wherein A is methoxy.
 5. The process of claim 3 whereein B is 5-chloro.
 6. The process of claim 2 wherein said starting material is a 3-carboxanilide and X and Y are each hydrogen and R1 is methyl.
 7. The process of claim 6 wherein R2 is 2-thiazolyl.
 8. The process of claim 6 wherein R2 is 2-pyridyl.
 9. The process of claim 6 wherein A is 2-chloro and B is 5-chloro.
 10. The process of claim 6 wherein A is 2-methoxy and B is 5-methoxy. 